Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris

Abstract Objective The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD)....

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Autores principales:	Ingrid Morales, Ricardo Puertas-Avendaño, Alberto Sanchez, Adrian Perez-Barreto, Clara Rodriguez-Sabate, Manuel Rodriguez
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Astrocyte Phagocytosis Parkinson’s disease Dying-back degeneration Medial forebrain bundle Spheroid Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/3d0202c695e94f52b84b5ed47935c4a1
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spelling	oai:doaj.org-article:3d0202c695e94f52b84b5ed47935c4a12021-11-08T11:03:25ZAstrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris10.1186/s40035-021-00262-12047-9158https://doaj.org/article/3d0202c695e94f52b84b5ed47935c4a12021-11-01T00:00:00Zhttps://doi.org/10.1186/s40035-021-00262-1https://doaj.org/toc/2047-9158Abstract Objective The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. Methods Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. Results The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. Conclusions The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.Ingrid MoralesRicardo Puertas-AvendañoAlberto SanchezAdrian Perez-BarretoClara Rodriguez-SabateManuel RodriguezBMCarticleAstrocytePhagocytosisParkinson’s diseaseDying-back degenerationMedial forebrain bundleSpheroidNeurology. Diseases of the nervous systemRC346-429ENTranslational Neurodegeneration, Vol 10, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Astrocyte Phagocytosis Parkinson’s disease Dying-back degeneration Medial forebrain bundle Spheroid Neurology. Diseases of the nervous system RC346-429
spellingShingle	Astrocyte Phagocytosis Parkinson’s disease Dying-back degeneration Medial forebrain bundle Spheroid Neurology. Diseases of the nervous system RC346-429 Ingrid Morales Ricardo Puertas-Avendaño Alberto Sanchez Adrian Perez-Barreto Clara Rodriguez-Sabate Manuel Rodriguez Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
description	Abstract Objective The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. Methods Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. Results The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. Conclusions The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.
format	article
author	Ingrid Morales Ricardo Puertas-Avendaño Alberto Sanchez Adrian Perez-Barreto Clara Rodriguez-Sabate Manuel Rodriguez
author_facet	Ingrid Morales Ricardo Puertas-Avendaño Alberto Sanchez Adrian Perez-Barreto Clara Rodriguez-Sabate Manuel Rodriguez
author_sort	Ingrid Morales
title	Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
title_short	Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
title_full	Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
title_fullStr	Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
title_full_unstemmed	Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris
title_sort	astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in parkinson’s disease: removing axonal debris
publisher	BMC
publishDate	2021
url	https://doaj.org/article/3d0202c695e94f52b84b5ed47935c4a1
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Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease: removing axonal debris

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